1. Field of the Invention
The present invention relates to a prophylactic/therapeutic agent for neurodegenerative diseases (such as polyglutamine diseases), as well as to a method for screening substances that are effective in the prevention/treatment of neurodegenerative diseases (such as polyglutamine diseases).
2. Description of the Related Art
Polyglutamine diseases, including Huntington's disease, are neurodegenerative diseases caused by an abnormally expanded polyglutamine tract in the causative gene products. To date, few substances have been reported to be effective in the prevention/treatment of polyglutamine diseases although there are some reports that suggest the effectiveness of creatine, a compound involved in muscle contraction, and minocycline, an apoptosis inhibitor, in a Huntington's disease mouse model. While it is widely suggested that apoptotic cell death occurs in the cell model of polyglutamine diseases, the actual clinical use of apoptosis inhibitors is associated with considerable difficulty.
Under such circumstances, much attention has been drawn to the fact that the abnormal polyglutamine expansion induces the formation of insoluble protein aggregates within the nuclei and, thus, the use of inhibitors of polyglutamine-induced protein aggregation in the prevention or treatment of polyglutamine diseases has been proposed. For example, Japanese Patent Application Laid-Open (JP-A) No. 2003-267874 discloses specific oligosaccharides, or compounds having an oligosaccharide moiety, that inhibit the protein aggregation induced by an abnormal polyglutamine expansion and can therefore be used in the prevention or treatment of polyglutamine diseases. Since the deposition of protein aggregates within neurons is a phenomenon observed not only in polyglutamine diseases, but also in Alzheimer's disease and other neurodegenerative diseases, inhibition of the protein aggregation within neurons is expected to provide a way to prevent or treat various neurodegenerative diseases.
HMGB protein family is a family of high mobility group (HMG) proteins. HMG proteins are a group of non-histone proteins that are extracted from chromatin with 0.35M NaCl and show a high mobility in electrophoresis. These proteins are present in the nuclei of all higher organisms and have highly conserved amino acid sequences among higher organisms. The proteins of HMGB family are abundant in the nuclei and are well conserved among different species, suggesting an important role of the HMGB family proteins in the nuclei. While the exact functions of HMGB family are still unknown, these proteins have two HMG boxes for DNA binding and have been reported to interact with transcription factors, site-specific recombinant proteins, DNA repair proteins, silencing complexes and viral proteins (see Agresti, A. et al., Curr. Opin. Genet Develop. 13, 170-178. (2003)) and have an acidic C-terminal domain rich in basic amino acids. It has also been reported that the HMGB proteins play a key role in the genomic DNA remodeling by being inserted between DNA and histone complexes (see Agresti, A. et al., Curr. Opin. Genet Develop. 13, 170-178. (2003), and Travers A. E. EMBO reports 4, 131-136. (2003)) and that these proteins facilitate nucleosome remodeling by binding preferentially to distorted DNA, bending DNA, loosening wrapped DNA and thus enhancing accessibility to chromatin-remodeling complexes (see Travers A. E. EMBO reports 4, 131-136. (2003)).